Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin-17 and Janus Kinase-Signal Transducers and Activators of Transcription Signaling

Objective: Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS.Methods: We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization.Results: Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 x 10(-5)) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-a (OR >39, p < 1.6 x 10(-3)) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 x 10(-5)), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 x 10(-3)), independent of type 1 diabetes (OR 1.05, p = 4.3 x 10(-7)), type 2 diabetes (OR 1.08, p = 2.3 x 10(-3)), inflammatory bowel disease (OR 1.11, p = 1.6 x 10(-11)), and vitamin D level (OR 0.75, p = 9.4 x 10(-3)).Interpretation: By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023

Automated summary

By using epidemiology and genetics, we have comprehensively studied the relationship between psoriasis and multiple sclerosis (MS). We found that psoriatic patients have a significantly higher risk of developing MS. Through genetic analysis, we identified shared genetic loci and pathways related to immune functions. Furthermore, we found that psoriasis has a causal effect on MS, independent of other risk factors.